Early detection of chronic kidney disease

INTRODUCTION — Chronic kidney disease (CKD) is a worldwide public health problem. In the United States, the prevalence of end-stage kidney disease (ESKD) is increasing [1,2]. Patients with ESKD consume a disproportionate share of health care resources [2-4] and experience significant mortality and morbidity and a reduced quality of life [3,5,6].

Identifying and managing patients who have early stages of CKD may slow or prevent the progression to ESKD and reduce cardiovascular complications [7,8].

This topic reviews recommendations for population-based CKD screening and case finding, which are collectively termed "early detection." Overviews of the epidemiology and management of CKD and its complications are discussed elsewhere. (See "Epidemiology of chronic kidney disease" and "Overview of the management of chronic kidney disease in adults".)

RATIONALE FOR EARLY DETECTION — The rationale for testing asymptomatic people for CKD is that earlier detection might allow for the implementation of therapeutic interventions and avoidance of inappropriate exposure to nephrotoxic agents, both of which may slow the progression of CKD to end-stage kidney disease (ESKD) [7,8]. The detection of CKD also identifies an important risk factor for cardiovascular disease (CVD). (See "Coronary artery disease and myocardial infarction in young people", section on 'Coronary risk factors' and "Prevalence of and risk factors for coronary heart disease in patients with diabetes mellitus".)

Early detection of CKD with reduced glomerular filtration rate (GFR) may also facilitate appropriate dosing of medications and allow timely preparation for kidney replacement, which may improve outcome [9]. (See "Overview of the management of chronic kidney disease in adults", section on 'Consequences of late referral'.)

CKD is generally under-recognized, particularly among certain patient subsets [10-14]. In one study of the National Health and Nutrition Examination Survey (NHANES) data from 2003 to 2004, among patients with estimated GFR (eGFR) 45 to 59 mL/minute/1.73 m², awareness of kidney disease was reported in only 9.2 percent [14]. Awareness was increased among those with proteinuria, diabetes, or hypertension and among men compared with women.

More recent data suggest that awareness of CKD depends on how the question is asked [15]. Asking multiple questions about the possible presence of kidney disease led to a higher apparent prevalence than when only one question was asked [15]. This suggests that earlier studies, which were based on a single question, may have underestimated the true prevalence of awareness. In addition, there is some evidence that the proportion of people with CKD who are aware of their kidney disease is increasing [14,16]. However, awareness of CKD appears lower than awareness of other chronic conditions such as dyslipidemia, hypertension, and diabetes [15].

APPROACH TO EARLY DETECTION

Case finding versus widespread population screening — We suggest a case-finding (or targeted) approach to early detection rather than population-based screening. Case finding is a strategy that tests for CKD only in people who are at increased risk. This approach more efficiently identifies individuals who may benefit from intervention and potentially reduces the risk of harms due to false-positive results of testing [17].

Although population-based screening would almost certainly detect individuals who have no identified risk factors but are at risk for progression to end-stage kidney disease (ESKD) [18,19], a very large number of individuals would need to be tested and treated in order to possibly prevent one case of ESKD [20-23].

This was demonstrated in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study, in which 40,854 individuals in the Netherlands aged 28 to 75 years were screened for increased urinary albumin excretion [18]. Almost one-half of the individuals who ultimately required kidney replacement therapy had moderately increased albuminuria [18]. Testing only high-risk individuals identified 55 percent of those with moderately increased albuminuria and 87 percent of those who progressed to ESKD. Because 40 to 50 percent of individuals with moderately increased albuminuria did not have risk factors for CKD, the authors advocated screening the general population rather than case finding. However, among 25,597 PREVEND participants who did not have any risk factors for CKD, there were only six cases of ESKD.

In addition, although the relatively low cost of testing urine for moderately increased albuminuria favors population-based screening, the total cost of such a program is actually higher since it includes the time and effort to collect specimens, the cost of confirmatory tests for treatment of a positive test, and the costs of monitoring and treatment of complications associated with interventions, as well as any false-positive results.

Finally, there is no direct evidence that a therapeutic intervention such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists decreases the risk of ESKD or a clinically significant loss of glomerular filtration rate (GFR) among individuals who have moderately increased albuminuria but no other risk factors.

In a cost-effectiveness analysis performed by the Centers for Disease Control and Prevention (CDC), CKD screening using a test for moderately increased albuminuria was cost effective only for individuals with diabetes or hypertension or aged older than 50 years [24].

However, in a subsequent systematic review, case-finding strategies for CKD were cost effective in patients with diabetes and hypertension and probably also in populations with higher incidences of CKD, rapid rates of progression, and more effective drug therapies [23]. Since African Americans are at higher risk for ESKD, case finding in this population may be more cost effective than in the general United States population [25,26]. Similar considerations apply to other specific populations, such as First Nations people in Canada. Despite this, in order to be economically attractive, any early detection strategy would need to improve clinical outcomes compared with the absence of such a strategy, which remains to be conclusively shown [27]. (See "Epidemiology of chronic kidney disease".)

CKD risk scores [28-30] could be helpful to identify people who might benefit from screening for early CKD. Although this approach was cost-effective [31] in one study, further external validation and association with outcomes is needed.

The US Preventive Services Task Force (USPSTF) has concluded that evidence is insufficient to assess benefits and screening of asymptomatic adults (excluding testing for and monitoring as part of the management of chronic diseases such as diabetes or hypertension) [32]. The American College of Physicians (ACP) recommends against screening for CKD in asymptomatic adults who do not have risk factors [33], although the American Society of Nephrology (ASN) strongly recommends regular screening for kidney disease, even in the absence of risk factors [34]. This discrepancy between recommendations from generalist and disease-based specialty organizations is also observed for many other conditions.

Who should be tested? — Adopting a case-finding strategy that restricts testing to people with risk factors for CKD appears to enrich the proportion of positive tests [35]. We believe that patients with risk factors for CKD should be evaluated with a urine test for albuminuria and a blood test for creatinine to estimate GFR. However, the ACP has recommended that patients with or without diabetes who are already taking either an ACE inhibitor or an angiotensin II receptor blocker (ARB) should not be tested for proteinuria [33], although this recommendation is controversial [36]. Patients who are at risk for glomerulonephritis should be screened for hematuria with a urinalysis. (See 'Methods of testing for CKD' below.)

We recommend that all individuals be assessed for CKD risk as part of routine health examinations [1,37]. This is consistent with recommendations of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines for CKD, which have been reviewed and endorsed by the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease [38] and the KDIGO 2019 Controversies Conference on early identification and intervention of CKD [39].

The presence of the following risk factors should trigger formal testing for CKD in adults [40]:

●History of diabetes, hypertension, cardiovascular disease, HIV or hepatitis C virus infection, malignancy, autoimmune diseases, nephrolithiasis, or recurrent urinary tract infections (UTIs).

●Origin from a specific population, such as First Nations people of Canada [41-44].

●Family history of kidney disease [45].

●Sickle cell trait (SCT) [40].

Formal testing for CKD may also be performed in people with multiple cardiovascular risk factors but without known CVD, although the number of risk factors that should prompt such testing is unknown (see "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach"). Evaluation for CKD may be of benefit among adults living in areas where CKD incidence is unusually high ("CKD hotspots"), such as certain regions of Central America, Sri Lanka, and the Balkans [46-49]. However, this will require further study before making geographically based recommendations for CKD testing [50].

Although some have proposed testing for CKD in all patients aged more than 60 years [37], this approach is not based on available evidence, and more data are needed before such screening is recommended. If an early detection approach is desired, the initiation, frequency, and discontinuation of testing for CKD should be individualized based on kidney and cardiovascular risk profiles and individual preferences, rather than at a specific chronological age. Moreover, in the setting of limited life expectancy, if CKD is detected, any change in treatment should carefully weigh the risks and benefits [39]. (See "Kidney palliative care: Conservative kidney management".)

Race/ethnicity, poor access to health care or low socioeconomic status, high-risk occupations, environmental exposures, genetic risk factors, prior acute kidney injury, and preeclampsia may also appropriately trigger testing for CKD [39].

Risk factors — The following risk factors should be considered when determining whether to test an asymptomatic patient for kidney disease:

●Diabetes, hypertension, and CVD – A history of diabetes, hypertension, or CVD confers the highest risk for developing CKD, and individuals who have such a history should be evaluated for CKD [37]. The CKD risk is discussed in individual topic reviews. (See "Overview of hypertension in adults", section on 'Secondary or contributing causes of hypertension' and "Chronic kidney disease and coronary heart disease".)

●Origin from specific populations – First Nations people of Canada, Native Americans, and Aboriginal Australians are at increased risk of CKD and kidney failure and may have reduced access to health services that in turn decrease the likelihood of opportunistic detection of previously unrecognized CKD [41-44]. This increases the theoretical appeal of case finding in this population, although whether such a strategy will lead to clinical benefit is as yet unproven.

●Sickle cell trait (SCT) – Observational studies demonstrate that adults with SCT have a significantly higher risk of CKD than those without SCT and that the magnitude of the excess risk appears clinically relevant. In one pooled analysis, the absolute risk of incident CKD was 8.5 percent higher over long-term follow-up among those with SCT as compared with those without (95% CI 5.1-12.3%) [40]. (See "Sickle cell disease effects on the kidney".)

●Other chronic illnesses including HIV, hepatitis C, or other chronic viral infections – Both chronic viral infection and retroviral treatment are associated with CKD. (See "Overview of kidney disease in patients with HIV" and "HIV-associated nephropathy (HIVAN)" and "Overview of kidney disease associated with hepatitis C virus infection".)

●Current or history of malignancy – Cancer or cancer treatment can cause acute kidney injury and CKD. (See "Overview of kidney disease in patients with cancer", section on 'Causes of CKD in patients with cancer'.)

●Nephrotoxic medication – Chronic use of nephrotoxic medications, such as nonsteroidal anti-inflammatory agents, lithium, and possibly proton pump inhibitors, confers a higher risk of CKD. (See "NSAIDs: Acute kidney injury", section on 'Risk of chronic kidney disease' and "Renal toxicity of lithium" and "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Kidney disease'.)

●Obesity – Observational studies have suggested that obesity may also be associated with CKD [51-58]. However, we generally do not routinely evaluate patients with obesity for CKD unless other indications are present.

●History of kidney disease during childhood – A nationwide population-based cohort study including 1,521,501 Israeli adolescents demonstrated an increased risk of ESKD (defined as starting dialysis or receiving a kidney transplant) among individuals with a history of childhood kidney disease [59]. Adolescents (mean age 17.7 years) were screened before compulsory military service between the years 1967 to 1997, and data were linked to the Israeli ESKD registry. Individuals were excluded from analysis if they had abnormal kidney function, hypertension, diabetes, systemic lupus erythematosus, vasculitis, any rheumatologic disease, or cancer.

A history of any kidney disease (including congenital anomalies of the kidney and urinary tract, pyelonephritis, and glomerular disease) was associated with increased risk of ESKD (hazard ratio 4.19, 95% CI 3.52-4.99). The magnitude of risk was independent of the type of kidney disease. Individuals with a history of childhood kidney disease also presented with ESKD at a younger age (42 years versus 49 years in individuals without such a history).

Specific details regarding the individual kidney diseases (such as age of initial presentation and medications and/or surgical interventions used during treatment) are lacking, which limits the interpretation of this observational study [60]. In addition, the study did not report imaging data, and it is possible that individuals with abnormal kidney imaging were included in the analysis; such individuals are considered by current criteria to have CKD, even in the absence of reduced kidney function (see "Definition and staging of chronic kidney disease in adults", section on 'Definition of CKD'). In addition, the absolute incidence of ESKD among adults with a history of kidney disease in childhood was very low (16.3 to 28.3 cases per 100,000 person-years).

Methods of testing for CKD — Patients who are selected for CKD evaluation should have a urine test for albumin and a blood test for creatinine to estimate GFR. The preferred testing strategy for albuminuria is measurement of the urine albumin-to-creatinine ratio in an untimed urinary sample. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Quantitative measurement'.)

Urinary albumin is more strongly associated with clinical outcomes than total urinary protein, and it is required to classify CKD according to KDIGO criteria [39].

Evaluating for hematuria with a urinalysis should be done in selected populations that are at increased risk for glomerulonephritis [37]. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

The estimated GFR (eGFR) and the threshold of <60 mL/min/1.73 m² that defines CKD may have limitations, particularly among older adults (see "The aging kidney" and "Assessment of kidney function"). Some have advocated for using serum creatinine and cystatin C measurements together for initial CKD diagnosis and staging. This diagnostic approach improves accuracy in people with true eGFR between 45 and 59 mL/min/1.73 m². People with CKD as identified by both serum creatinine and cystatin C have a higher risk of cardiovascular events, kidney failure, and death than those with CKD identified by serum creatinine alone. However, the advantages of combination testing are substantially attenuated at lower true eGFR. Thus, it might be preferable to use a lower GFR threshold for early detection strategies, such as <45 mL/min/1.73 m², since the combination testing strategy adds complexity and cost that may be particularly challenging for resource-limited countries [38,39]. Additional studies are needed to determine the optimal testing strategy for early detection of CKD.

Depending on the presence of particular risk factors, additional testing may be required. As an example, an individual with a family history of polycystic kidney disease may require an ultrasound.

Once the diagnosis of CKD is established, the cause and/or potentially reversible factors should be identified and treated. (See "Chronic kidney disease (newly identified): Clinical presentation and diagnostic approach in adults".)

In addition, CKD should be staged according to the KDIGO revised classification (table 1) [38]. (See "Overview of the management of chronic kidney disease in adults", section on 'Definition and classification'.)

This classification is based on laboratory evaluation of the severity of kidney disease, association of level of kidney function with complications, and stratification of risks for loss of kidney function and development of CVD.

Frequency of testing — The frequency of testing for CKD in high-risk groups has not been rigorously studied, and recommendations are opinion based. The National Kidney Disease Education Program (NKDEP) of the National Institutes of Health (NIH) and the UK's National Institute for Health Research recommend yearly testing among patients with diabetes [61]. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Monitoring for increased urinary albumin excretion'.)

Patients with hypertension should be tested at diagnosis, upon initiation of therapy, and every three years thereafter. Individuals with a family history of CKD should be tested every three years. Individuals with other risk factors may be tested less frequently [62].

The KDIGO Controversies Conference concluded that the frequency of repeat testing could be based on each individual's risk of developing CKD. Risk equations that estimate five-year CKD probabilities could be used to guide the timing of subsequent testing [30,39].

EARLY DETECTION PROGRAMS — The National Kidney Foundation (NKF)-sponsored Kidney Early Evaluation Program (KEEP) was a screening program targeted at individuals 18 years or older at high risk for developing CKD because they have diabetes, hypertension, and/or first-order relatives with those conditions or kidney disease. KEEP offered free blood and urine testing, on-site consultation by a clinician, referrals, and additional follow-up for those whose test results were outside normal ranges [63,64]. Data collected included age, family history, height, weight, blood pressure, the presence of moderately increased albuminuria, pyuria, hematuria, plasma glucose, and serum creatinine concentration [65]. Among 89,622 KEEP participants, the overall CKD prevalence was 26 percent, of which 17 percent had stage 3 and 1 percent stage 4 or 5 [66].

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has also launched the National Kidney Disease Education Program (NKDEP) [67]. This program is designed to increase awareness of the risk for CKD, especially among providers for high-risk groups, and to develop straightforward management steps for primary care clinicians based upon the formal guidelines being developed by the Kidney Disease Outcomes Quality Initiative (KDOQI) [67]. Similar strategies have been undertaken globally, including adaptations of the KEEP program in Japan and Mexico, the SeeCKD program in Canada, and the Kidney Evaluation for You program in Australia [35,68-70].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Identifying and managing patients who have early stages of chronic kidney disease (CKD) may slow or prevent the progression to end-stage kidney disease (ESKD) and reduce cardiovascular complications. Early detection of CKD might also facilitate appropriate dosing of medications and allow timely preparation for kidney replacement, which may improve outcome. (See 'Introduction' above and 'Rationale for early detection' above.)

●We suggest evaluating high-risk individuals for CKD, which is termed "case-finding" (Grade 2C). Important risk factors for CKD include diabetes, hypertension, and cardiovascular disease (CVD); other risk factors to be considered include a positive family history for kidney disease, human immunodeficiency virus (HIV) or hepatitis C virus infection, sickle cell trait (SCT), malignancy, autoimmune diseases, nephrolithiasis, and recurrent urinary tract infections (UTIs). (See 'Approach to early detection' above.)

●Patients who are selected for CKD evaluation should have a urine test for albumin in a random urine sample and a blood test for creatinine to estimate glomerular filtration rate (GFR). Additional testing, such as kidney ultrasonography, may be required in selected individuals (eg, in patients with a family history of polycystic kidney disease). (See 'Methods of testing for CKD' above.)

●The frequency of testing for CKD in high-risk groups has not been rigorously studied, and recommendations are opinion based. We suggest that patients with diabetes are tested on a yearly basis and patients with hypertension at diagnosis, upon initiation of therapy, and every three years thereafter. Individuals with a family history of CKD should be tested every three years. Risk equations that estimate five-year CKD probabilities could also guide the timing of subsequent testing. (See 'Frequency of testing' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Brian JG Pereira, MD, who contributed to earlier versions of this topic review.